Gilvocarcin M (1) shows the key structural features of a growing class of aryl C-glycoside antibiotics which share a common aromatic nucleus, 6H-benzo[d]naphtho[1,2-b]pyran-6-one, to which various rare sugars are connected through a C-C bond. The attractiveness of these compounds as synthetic targets is due to the challenges presented by their unusual C-glycoside structures linked to the highly functionalized skeleta, and because some of the members show significant antitumor activity with exceptionally low toxicity. The reported synthetic endeavors, however, have addressed only the aglycon portion (i.e., defucogilvocarcin), and the synthesis of the full structure of natural product with the sugar moiety remains a challenging problem. In the present study, we accomplished the first total synthesis of both enantiomers of gilvocarcin M (1). The synthetic route is exceedingly concise and effective by virtue of two selective conversions. (1) O→C-Glycoside rearrangement: Coupling of the acetate 19, derived from L-fucose, with the phenol 20 proceeded regioselectively to give C-glycoside 21. Some silver perchlorate reagents or Cp_2HfCl_2-AgClO_4 effected stereoselective coupling to give the desired, contra-steric, α-L-C-glycoside 21-α. (2) Benzyne-furan cycloaddition: The benzyne, generated from ortho-haloaryl triflate 22 by halogen-lithium exchange, underwent [4+2]-cycloaddition with 2-methoxyfuran (17) to yield the 1,4,5-naphthalenetriol derivative 23 with high regioselectivity. Acylation of 23 with the acid chloride 24 followed by a Pd-catalyzed cyclization and final deprotection gave 1. The overall yield was 41% for six steps. Synthetic 1 ([α]^<23>D+209°) turned out to be the enantiomer of the natural gilvocarcin M ([α]^<20>D-209°). The natural enantioner of 1 was synthesized from D-fucose by the same scheme thereby establishing the D-absolute configuration of the natural product.
